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Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) Functions to Promote Uterine Decidual Angiogenesis during Early Pregnancy in the Mouse

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (N.C.D., H.T., R.G., C.M.S., J.K., M.S., R.C.Z.), and Department of Pathology (J.K.), Columbia University, New York, New York 10032; ImClone Systems, Inc. (B.P.), New York, New York 10014; and Schering-Plough Corporation (D.J.H.), Kenilworth, New Jersey 07033

Address all correspondence to: Nataki C. Douglas, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Columbia University, 622 West 168th Street, PH 16-E, New York, New York 10032. E-mail: nd2058{at}columbia.edu. Address reprint requests to: Ralf C. Zimmermann at the address above. E-mail: rcz3{at}columbia.edu.

Implantation of an embryo induces rapid proliferation and differentiation of uterine stromal cells, forming a new structure, the decidua. One salient feature of decidua formation is a marked increase in maternal angiogenesis. Vascular endothelial growth factor (VEGF)-dependent pathways are active in the ovary, uterus, and embryo, and inactivation of VEGF function in any of these structures might prevent normal pregnancy development. We hypothesized that decidual angiogenesis is regulated by VEGF acting through specific VEGF receptors (VEGFRs). To test this hypothesis, we developed a murine pregnancy model in which systemic administration of a receptor-blocking antibody would act specifically on uterine angiogenesis and not on ovarian or embryonic angiogenesis. In our model, ovarian function was replaced with exogenous progesterone, and blocking antibodies were administered prior to embryonic expression of VEGFRs. After administration of a single dose of the anti-VEGFR-2 antibody during the peri-implantation period, no embryos were detected on embryonic d 10.5. The pregnancy was disrupted because of a significant reduction in decidual angiogenesis, which under physiological conditions peaks on embryonic d 5.5 and 6.5. Inactivation of VEGFR-3 reduced angiogenesis in the primary decidual zone, whereas administration of VEGFR-1 blocking antibodies had no effect. Pregnancy was not disrupted after administration of anti-VEGFR-3 or anti-VEGFR-1 antibodies. Thus, the VEGF/VEGFR-2 pathway plays a key role in the maintenance of early pregnancy through its regulation of peri-implantation angiogenesis in the uterine decidua. This newly formed decidual vasculature serves as the first exchange apparatus for the developing embryo until the placenta becomes functionally active.